The present invention relates to an agent for the expression of long-term potentiation of synaptic transmission, an anti-dementia agent and an anti-amnesia agent, all of which containing a compound having a brain somatostatin activation property. More particularly, the present invention relates to an agent for the expression of long-term potentiation of synaptic transmission, an anti-dementia agent and an anti-amnesia agent, all of which containing a compound exerting a brain somatostatin release promoting action through suppression of the negative feedback mechanism of brain somatostatin release. The present invention moreover relates to a method for expressing long-term potentiation of synaptic transmission, a method for the treatment and/or prophylaxis of dementia and amnesia, and a screening method of these drugs using a somatostatin releasing property as an index.
The hippocampal function is said to be responsible for learning and memory. When an input neuron of the hippocampus is stimulated for a short time at high frequency, the efficiency of synaptic transmission continues to increase for a long time thereafter. This phenomenon is called long-term potentiation (hereinafter also referred to as LTP) of synaptic transmission, and has been recognized as a cellular model of learning and memory (T. V. P. Bliss and G. L. Collingdidge, Nature vol. 361, p.31, 1993). There is a demand for further elucidation of the mechanism of the LTP and the relation thereof with learning and memory. Also, a search for a compound having a property of long-term potentiation of synaptic transmission has been desired.
Somatostatin has been known for quite a long time as a hypothalamic hormone capable of suppressing the secretion of somatotropin from the pituitary gland. It has been recently found that it is also present in the cerebral cortex and the hippocampus, that are important cerebral sites for memory and learning, at high concentrations, playing an important role in memory and learning as a neuromodulator.
As a result of the intensive studies of the present inventors, it has been newly found that a compound having a brain somatostatin release promotion property expresses long-term potentiation of synaptic transmission. Based on this new finding, we have found that administration of a compound having a brain somatostatin release promoting property leads to the prophylaxis and/or treatment of cerebral diseases such as dementia, amnesia, manic-depressive psychosis, schizophrenia, Parkinson""s disease, psychosomatic disease, and the like, which resulted in the completion of the present invention.
Accordingly, the present invention provides the following.
(1) An agent for expression of long-term potentiation of synaptic transmission, which comprises a compound having a brain somatostatin activation property as an active ingredient.
(2) The agent for expression of long-term potentiation of synaptic transmission of (1), wherein the compound exerts an action to promote a release of brain somatostatin through suppression of a negative feedback mechanism of brain somatostatin release.
(3) The agent for expression of long-term potentiation of synaptic transmission of (1) or (2), which is an agent for the prophylaxis or treatment of cerebral diseases.
(4) The agent for expression of long-term potentiation of synaptic transmission of (3), which is an agent for the prophylaxis or treatment of dementia or amnesia.
(5) A method for expressing long-term potentiation of synaptic transmission, comprising administering an effective amount of a compound having a brain somatostatin activating property.
(6) The method for expressing long-term potentiation of synaptic transmission of (5), wherein the compound exerts an action to promote a release of brain somatostatin through suppression of a negative feedback mechanism of brain somatostatin release.
(7) The method for expressing long-term potentiation of synaptic transmission of (5) or (6), which is a method for the prophylaxis or treatment of cerebral diseases.
(8) The method for expressing long-term potentiation of synaptic transmission of (5) or (6), which is a method for the prophylaxis and/or treatment of dementia or amnesia
(9) Use of a compound having a brain somatostatin activation property for the production of an agent for the expression of long-term potentiation of synaptic transmission.
(10) The use of a compound having a brain somatostatin activation property according to (9), wherein the compound exerts an action to promote a release of brain somatostatin through suppression of a negative feedback mechanism of brain somatostatin release.
(11) The use of a compound having a brain somatostatin activation property according to (9) or (10), which is for the production of an agent for the prophylaxis and/or treatment of cerebral diseases.
(12) The use of a compound having a brain somatostatin activation property according to (9) or (10), which is for the production of an agent for the prophylaxis and/or treatment of dementia or amnesia.
(13) A method for screening an agent for expression of long-term potentiation of synaptic transmission, which comprises using a somatostatin releasing action as an index
(14) The screening method of (13), which is a screening method of an anti-dementia agent or anti-amnesia agent.
(15) A method for screening an agent for expression of long-term potentiation of synaptic transmission, which comprises stimulating hippocampal slices, bringing a hippocampal slice into contact with a test compound, measuring an amount of somatostatin released from the hippocampal slice and/or a release time thereof, measuring an amount of somatostatin released from a hippocampal slice and/or a release time thereof in the absence of a contact with the test compound, and comparing the amounts and/or the times to calculate the amount of somatostatin released from the hippocampal slice and/or the release time thereof caused by the contact with the test compound.
(16) The screening method according to (15), which is a screening method of an anti-dementia agent or anti-amnesia agent.
(17) The agent for expression of long-term potentiation of synaptic transmission of (1), wherein the compound having the brain somatostatin activation property is a compound obtained by the screening method of any of (13) to (16).
(18) The method for expressing long-term potentiation of synaptic transmission according to (5), wherein the compound having the brain somatostatin activation property is a compound obtained by the screening method of any of (13) to (16).
(19) The use of a compound having a brain somatostatin activation property according to (9), wherein the compound having the brain somatostatin activation property is obtained by the screening method of any of (13) to (16).
(20) A compound selected by the screening method described in any of (13) to (16).